This multi-institutional Program Project from the Emory University School of Medicine focuses on the elucidation of the biology and molecular pathways involved in the interaction between stromal cells of the bone or the prostate and malignant prostate cancer cells. The overarching theme of this Program Project is that prostate cancer cell interaction with its microenvironment determine tumor growth, invasion, and metastasis in an organ-specific manner. This is manifested in clinical prostate cancer bone metastasis where the proliferation of both tumor epithelium and surrounding bone osteoblasts are accelerated. By understanding the molecular basis of this interaction, novel therapeutic targeting strategies can be developed to treat prostate cancer bone metastasis. This Program Project comprises of 3 Projects and 3 Cores and is organized to achieve synergy among the individual scientists who already have an established track record of prior research collaborations. Specific areas of investigation are: Project 1-Chung: the analysis of extracellular matrix (ECM) and integrin interaction in prostate cancer growth and metastasis; Project 2-Farach-Carson: the assessment of the roles of heparan sulfate proteoglycan (HSPG), heparin binding (HB) growth factors and their receptors in prostate cancer bone metastasis; Project 3-Petros: the determination of the effect of mitochondrial DNA (mtDNA) mutations on prostate cancer growth and metastasis, with specific focus on the anti-apoptotic function of mtDNA mutations in prostate cancer cells. Each of the projects has its own targeting theme and collaboratively will interact and achieve the goal of developing mechanism-based rational therapeutic approaches for the treatment of prostate cancer bone metastasis. This Program Project is supported by three Cores: the Administrative and Biostatistical Core A-Chung, the Animal and Tissue Culture Core B-Martin and the Pathology and Laboratory Support Core C-Amin. The ultimate goal of this Program Project is to develop novel diagnostic, prognostic and treatment modalities based on a mechanistic understanding of prostate tumor and prostate and bone stroma interaction.